title: Differential regulation of chemokines by IL-17 in colonic epithelial cells.
abstract: The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-alpha-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-alpha for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-alpha in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.
authors.affiliation: Biomedical Sciences Division, University of California, Riverside, CA 92521, USA.
authors.forename: Jimmy W
authors.initials: JW
authors.lastname: Lee
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kattah
authors.forename: Sawsan
authors.initials: S
authors.lastname: Youssef
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Kathryn
authors.initials: K
authors.lastname: DeFea
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Straus
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors; D054371:Chemokine CXCL11 / Q000037:antagonists & inhibitors; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C108355:CCL20 protein, human; C483024:CCL5 protein, human; C475829:CXCL1 protein, human; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C508606:CXCL8 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D018925:Chemokines; D020381:Interleukin-17; D016209:Interleukin-8; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha